Murine Dishevelled 3 Functions in Redundant Pathways with Dishevelled 1 and 2 in Normal Cardiac Outflow Tract, Cochlea, and Neural Tube Development

Dishevelled (Dvl) proteins are important signaling components of both the canonical β-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3−/− mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3−/− and LtapLp/+ mutants, Dvl3+/−;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant

Murine Dishevelled 3 Functions in Redundant Pathways with Dishevelled 1 and 2 in Normal Cardiac Outflow Tract, Cochlea, and Neural Tube Development

Dishevelled (Dvl) proteins are important signaling components of both the canonical β-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3−/− mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3−/− and LtapLp/+ mutants, Dvl3+/−;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant

Xenopus Pkdcc1 and Pkdcc2 Are Two New Tyrosine Kinases Involved in the Regulation of JNK Dependent Wnt/PCP Signaling Pathway

Protein Kinase Domain Containing, Cytoplasmic (PKDCC) is a protein kinase which has been implicated in longitudinal bone growth through regulation of chondrocytes formation. Nevertheless, the mechanism by which this occurs remains unknown. Here, we identified two new members of the PKDCC family, Pkdcc1 and Pkdcc2 from Xenopus laevis. Interestingly, our knockdown experiments revealed that these two proteins are both involved on blastopore and neural tube closure during gastrula and neurula stages, respectively. In vertebrates, tissue polarity and cell movement observed during gastrulation and neural tube closure are controlled by Wnt/Planar Cell Polarity (PCP) molecular pathway. Our results showed that Pkdcc1 and Pkdcc2 promote the recruitment of Dvl to the plasma membrane. But surprisingly, they revealed different roles in the induction of a luciferase reporter under the control of Atf2 promoter. While Pkdcc1 induces Atf2 expression, Pkdcc2 does not, and furthermore inhibits its normal induction by Wnt11 and Wnt5a. Altogether our data show, for the first time, that members of the PKDCC family are involved in the regulation of JNK dependent Wnt/PCP signaling pathway.Fundacao Ciencia e Tecnologia - IP; IBB/CBME, LA [PTDC/BIA-BCM/69912/2006, Pest-OE/EQB/LA0023/2013]; FCTinfo:eu-repo/semantics/publishedVersio

The efficacy of technetium-99m ciprofloxacin (Infecton) imaging in suspected orthopaedic infection: A comparison with sequential bone/gallium imaging

PubMedID: 11504078Technetium-99m ciprofloxacin (Infecton) has recently become established as a new radiopharmaceutical for the imaging of infection. This study was performed to determine the value of Infecton imaging in demonstrating orthopaedic infection and to compare the results with bone/gallium imaging. Twenty-two patients (12 female, 10 male; mean age 51.7±16.8 years) with suspected orthopaedic infective conditions were included in the study. The patients underwent three scintigraphic studies in the following sequence: 740 MBq 99mTc-methylene diphosphonate (MDP) three-phase bone scintigraphy; at least 2 days later, 370 MBq Infecton scan at 1-4 h; and finally, 185 MBq gallium-67 scintigraphy. 67Ga imaging could not be performed on four patients. All images were blindly interpreted by two independent observers. The final diagnosis was made by consensus when the readings were different. Interpretation of the early and late Infecton images was made separately, with visual findings being classified according to a four-grade scale (0, +, ++, +++). Images graded 0 and +, and also those regions which showed a decrease in uptake grade on late images as compared with early images, were classified as negative for infection; grades ++ and +++ were classified as positive. Bone/gallium images were considered positive when the images were spatially incongruent or when gallium uptake was more intense than that of 99mTc-MDP. The diagnosis was confirmed by intraoperative microbiological or histological findings, or by the presence of gross purulence. The sensitivity of Infecton imaging was found to be 85%, the specificity 92% and the accuracy 88%, as compared to figures of 78%, 100% and 90%, respectively, for bone/gallium imaging. Although the two modalities showed a similar clinical yield, the easy availability of Infecton and the short investigation time make Infecton imaging the better option for the detection of orthopaedic infection

Salt stress induces endoplasmic reticulum stress-responsive genes in a grapevine rootstock

Grapevines, although adapted to occasional drought or salt stress, are relatively sensitive to growth- and yield-limiting salinity stress. To understand the molecular mechanisms of salt tolerance and endoplasmic reticulum (ER) stress and identify genes commonly regulated by both stresses in grapevine, we investigated transcript profiles in leaves of the salt-tolerant grapevine rootstock 1616C under salt- and ER-stress. Among 1643 differentially expressed transcripts at 6 h post-treatment in leaves, 29 were unique to ER stress, 378 were unique to salt stress, and 16 were common to both stresses. At 24 h post-treatment, 243 transcripts were unique to ER stress, 1150 were unique to salt stress, and 168 were common to both stresses. GO term analysis identified genes in categories including 'oxidative stress', 'protein folding', 'transmembrane transport', 'protein phosphorylation', 'lipid transport', 'proteolysis', 'photosynthesis', and 'regulation of transcription'. The expression of genes encoding transporters, transcription factors, and proteins involved in hormone biosynthesis increased in response to both ER and salt stresses. KEGG pathway analysis of differentially expressed genes for both ER and salt stress were divided into four main categories including; carbohydrate metabolism, amino acid metabolism, signal transduction and lipid metabolism. Differential expression of several genes was confirmed by qRT-PCR analysis, which validated our microarray results. We identified transcripts for genes that might be involved in salt tolerance and also many genes differentially expressed under both ER and salt stresses. Our results could provide new insights into the mechanisms of salt tolerance and ER stress in plants and should be useful for genetic improvement of salt tolerance in grapevine

Spatial information of soil hydraulic conductivity and performance of cokriging over kriging in a semi-arid basin scale

Unlike the studies in small parcels by systematic measurements, the spatial variability of soil properties is expected to increase in those over relatively large areas or scales. Spatial variability of soil hydraulic conductivity (K (h)) is of significance for the environmental processes, such as soil erosion, plant growth, transport of the plant nutrients in a soil profile and ground water levels. However, its variability is not much and sufficiently known at basin scale. A study of testing the performance of cokriging of K (h) compared with that of kriging was conducted in the catchment area of Saraykoy II Irrigation Dam in CankA +/- rA +/-, Turkey. A total of 300 soil surface samples (0-10 cm) were collected from the catchment with irregular intervals. Of the selected soil properties, because the water-stable aggregates (WSA) indicated the highest relationship with the hydraulic conductivity by the Pearson correlation analysis, it is used as an auxiliary variable to predict K (h) by the cokriging procedure. In addition, the sampling density was reduced randomly to n = 175, n = 150, n = 75 and n = 50 for K (h) to determine if the superiority of cokriging over kriging would exist. Statistically, the results showed that all reduced K (h) was as good as the complete K (h) when its auxiliary relations with WSA were used in cokriging. Particularly, the results of the "Relative Reduction in MSE" (RMSE) revealed that the reduced data set of n = 75 produced the most accurate map than the others. In this basin-scaled study, there was a clear superiority of the cokriging procedure by the reduction in data although a very undulating topography and topographically different aspects, two different land uses with non-uniform vegetation density, different parent materials and soil textures were present in the area. Hence, using the statistically significant auxiliary relationship between K (h) and WSA might bring about a very useful data set for watershed hydrological researches

Adherence to GOLD guideline treatment recommendations among pulmonologists in Turkey

Elif Sen,1 Salih Zeki Guclu,2 Isil Kibar,3 Ulku Ocal,4 Veysel Yilmaz,5 Onur Celik,6 Filiz Cimen,7 Fusun Topcu,8 Meltem Orhun,9 Hikmet Tereci,10 Aylin Konya,11 Idilhan Ar,11 Sevgi Saryal11Department of Pulmonary Diseases, Ankara University School of Medicine, Ankara, 2Pulmonary Diseases Department, Izmir Dr Suat Seren Surgery Training and Research Hospital, Izmir, 3Pulmonary Diseases Department, Istanbul Hospital, Istanbul, 4Pulmonary Diseases Department, Adana Prof Dr Nusret Karasu Pulmonary Diseases Hospital, Adana, 5Pulmonary Diseases Department, Yedikule Pulmonary Diseases and Surgery Training and Research Hospital, Istanbul, 6Pulmonary Diseases Department, Nihat Kitapçi Pulmonary Diseases and Surgery Hospital, Erzurum, 7Pulmonary Diseases Department, Atatürk Pulmonary Diseases and Surgery Training and Research Hospital, Ankara, 8Department of Pulmonary Diseases, Dicle University School of Medicine, Diyarbakir, 9Pulmonary Diseases Department, Uskudar State Hospital, Istanbul, 10Pulmonary Diseases Department, Samsun Pulmonary Diseases and Thoracic Surgery Hospital, 11Pulmonary Diseases Department, Novartis Pharmaceuticals, Istanbul, TurkeyBackground: Low adherence to Global initiative for chronic Obstructive Lung Disease (GOLD) guideline recommendations has been reported worldwide. There has been no study on the adherence to GOLD guidelines for COPD treatment in Turkey.Objectives: To investigate the rates of adherence to GOLD 2010 guidelines for COPD treatment among pulmonologists.Design: A multi-center, cross-sectional, observational study was carried out in eleven pulmonary outpatient clinics across Turkey. Adherence to GOLD was evaluated through hospital records. Demographic and clinical data were recorded.Results: Study included 719 patients (mean age: 62.9±9.7 years; males 85.4%) of whom 16 was classified as GOLD Stage I, 238 as II, 346 as III, and 119 as IV, and only 59.5% received appropriate treatment. Rates of guideline adherence varied across GOLD stages (I, 6.3%; II, 14.7%;  III, 84.4%; and IV, 84%). Causes of inappropriate therapies were overtreatment (Stage I, 100% and Stage II, 91.1%), undertreatment (Stage III, 3.3% and Stage IV, 10.9%) and lack of treatment (Stage II, 3.8%; Stage III, 2.3%; and Stage IV, 5.9%). The most preferred regimen (43.4%) was long-acting β2-agonist-inhaled corticosteroid-long-acting muscarinic antagonist. Overall, 614 patients (89%) received treatment containing inhaled corticosteroid.Conclusion: Pulmonologists in Turkey have low rates of adherence to GOLD guidelines in COPD treatment. Inappropriateness of therapies was due to overtreatment in early stages and excessive use of inhaled corticosteroid (ICS) in all disease stages.Keywords: adherence, COPD, Global initiative for chronic Obstructive Lung Disease guidelines, treatment approach, Turkey, overtreatment, inhaled corticosteroi

Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping

HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families of French, Spanish, African and Malaysian origins. Multipoint linkage analysis in all 29 families generated a peak lod score of 53.5 at D13S1835 with a 1 lod unit support interval spanning 1.8 cM. Recombination mapping placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbruck equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively

Systemic Phaeohyphomycosis due to Exophiala (Wangiella) in an Immunocompetent Child

We report a rare case of systemic lymphadenitis and hepatic involvement due to Exophiala (Wangiella) dermatitidis in a pediatric patient. An 8-year-old immunocompetent boy with chronic fever was examined through the use of sonography and CT scan which demonstrated cervical and mesenteric lymph node enlargement and numerous small hepatic lesions. The etiologic agent was isolated by means of lymph node aspiration. The fungus was identified by its morphological characteristics and through DNA sequencing of the internal transcribed spacer region of rDNA. Despite initial amphotericin B and voriconazole therapy, the child's jaundice subsided and he died 7 months later. In addition to pathogenic aspects of Exophiala dermatitidis, the diagnostic approaches and relevant therapeutic strategies are discussed.WoSScopu